The aims of this proposal are to discover new reactivity in addition reactions to carbonyl compounds, at times in the context of the total synthesis of natural products. Specific aims include completion of the synthesis of the oxo-polyene macrolide antibiotic RK-397. We have prepared a late stage intermediate and in the next funding period, we will complete this synthesis. We will also study an intramolecular vinylogous aldol reaction similar to the Yamamoto intermolecular vinylogous aldol and we will apply this method to the synthesis of the cytotoxic macrolide, arenolide. We will also study a new strategy for conducting intramolecular aldol reactions based on using C-silylated esters as the nucleophilic component. These compounds are compatible with aldehydes and should react only upon activation. We have also developed an interesting asymmetric O-nucleophilic catalyst for enantioselective acyl transfer in the past funding period. This catalyst currently displays s-values of up to 31 for the methanolysis of alpha-acetoxy N- acylthiazolidinethiones. We will explore this catalyst system in the upcoming funding period and delineate its scope and limitations.